The long-term objective of this work is to determine how shed syndecan-1 regulates tumor behavior and to use this knowledge to develop new therapies for cancer. We have demonstrated that shed syndecan-1 drives tumor growth in vivo and promotes a hyperinvasive phenotype in vitro. Additionally, shed syndecan-1 in concert with VEGF causes increased phosphorylation of ERK in endothelial cells leading to increased cell proliferation and invasion. I have discovered that shed syndecan-1 binds to the surface of cells and translocates to the nucleus. I hypothesize that shed syndecan-1 activates cell surface receptors (integrins, receptor tyrosine kinases) and when translocated to the nucleus it decreases histone acetyltransferase (HAT) activity to promote an aggressive tumor phenotype. To address this intriguing mechanism of tumor-host crosstalk mediated by shed syndecan-1, the following aims have been devised to determine the novel role of shed syndecan-1 at the cell surface and within the nucleus of tumor and host cells. Aim 1 will determine which cell surface receptors shed syndecan-1 interacts with and activates and whether inhibiting these receptors abrogates the aggressive phenotype. Aim 2 will determine if shed syndecan-1 in the nucleus promotes aggressive tumor behavior. We will determine whether shed syndecan-1 decreases HAT activity and whether its interaction with cell surface receptors is a prerequisite for its translocation to the nucleus. This proposed work will further elucidate the role of shed syndecan-1 in cancer and, by exploring the nuclear function of shed syndecan-1, open a new area of research in the proteoglycan field. In addition, this work will further our understanding o the pathobiology of myeloma thereby aiding discovery of new therapeutic approaches. Shed syndecan-1 is present at high concentrations in the serum of myeloma patients and is an indicator of poor prognosis. This project is designed to provide new understanding of how shed syndecan-1 controls cellular behavior by addressing its role at the cell surface and within the nucleus of tumor and host cells. Results could lead to new therapeutic strategies for the treatment of myeloma and other cancers.